Following experimental stroke, the recovering brain is vulnerable to lipoxygenase-dependent semaphorin signaling

摘要: Recovery from stroke is limited, in part, by an inhibitory environment the postischemic brain, but factors preventing successful remodeling are not well known. Using cultured cortical neurons mice, brain endothelial cells, and a mouse model of ischemic stroke, we show that signaling axon guidance molecule Sema3A via eicosanoid second messengers can contribute to this environment. Either 90 nM recombinant Sema3A, or 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE 12-HPETE at 300 nM, block extension compared solvent controls, decrease tube formation cells. The effect reversed inhibiting 12/15-LOX, derived 12/15-LOX-knockout mice insensitive Sema3A. Following middle cerebral artery occlusion induce immunohistochemistry shows both 12/15-LOX increased cortex up 2 wk. To determine whether Sema3A-dependent damage pathway activated following ischemia, injected into striatum. alone did cause injury normal brains. But when brains, 79%, again, was inhibition. Our findings suggest blocking semaphorin should be investigated as therapeutic strategy improve recovery.—Pekcec, A., Yigitkanli, K., Jung, J. E., Pallast, S., Xing, C., Antipenko, Minchenko, M., Nikolov, D. B., Holman, T. R., Lo, E. H.,van Leyen, K. experimental recovering vulnerable lipoxygenase-dependent signaling.